A paucity of functional -cells is a central feature of type 1 and type 2 diabetes and an urgent question in islet biology relates to plasticity of -cell mass in the long-term goal of developing strategies to treat both forms of the disease. This application is focused on the role of growth factors, especially insulin and IGF-I receptors and proteins in their signaling pathway, in regulation of -cell proliferation, apoptosis and secretory function. We use unique genetic mouse models lacking one or more proteins in the insulin/IGF-I signaling pathway in -cells and complement with studies in cell lines and primary islets derived from the knockouts for in vitro and ex vivo experiments. Based on Preliminary Data we seek to continue our studies with the following Specific Aims: Aim 1: Determine the role of insulin/IGF-I signaling in proinsulin processing and test the hypothesis that an intact insulin/IRS-2 pathway is essential for appropriate proinsulin processing. Aim 2: Define the alterations in endoplasmic reticulum (ER) stress in cells lacking proteins in the insulin signaling pathway and test the hypothesis that the insulin/IRS-2 pathway is essential to limit ER stress in cells: Our preliminary data indicates a direct role for the insulin receptor and IRS-2, but not IRS-1, in ER stress responses in cells. We plan to dissect the mechanisms and pathways that underlie enhanced ER stress in the context of insulin/IRS-2 signaling with a focus on IRE-1a and contrast the findings with the pathways mediated by IRS-1. Aim 3: Dissect the mechanisms that link the insulin/IGF-I signaling with proteins involved in the -cell growth response to insulin resistance: Our preliminary data using in vivo approaches builds on previous work and indicates critical roles for cycling D2 and Px-1 in the compensatory islet growth response to insulin resistance. We will focus on these two proteins and explore their link with FoxO1 to dissect the mechanisms that underlie the proliferation responses especially in the context of differences between insulin and IGF-1 signaling. Together we believe these studies will provide novel insights into the role of growth factors in the regulation of -cell proliferation and apoptosis. PUBLIC HEALTH RELEVANCE: This project is aimed at understanding the mechanism(s) that underlie the proliferation and survival of beta cells with a focus on the insulin and insulin-like growth factor pathways. Using genetically engineered mouse models and primary islets and beta cell lines derived from the knockout mice we will focus on identifying the pathways that promote beta cell regeneration with the long-term goal of developing therapeutic approaches to counter the loss of beta cells in both type 1 and type 2 diabetes.